Luminal-type breast cancers are preferentially treated with hormonal therapy, while not a few patients relapse. The mechanisms of the hormone refractoriness have been investigated by numerous studies so far. However, it has not been fully clarified yet. We have been investigating the mechanisms using cancer specimens and cell lines by monitoring transcription activity of estrogen receptor (ER). We so far established six different types of cell lines which mimic aromatase inhibitor (AI) resistance from ERE-GFP introduced ER-positive breast cancer cell lines. They revealed that multiple and alternative ER activating pathways were involved in the resistance. The mechanisms are currently proposed to be three categories, such as (1) an aromatase-independent estrogen-producing pathway, (2) estrogen-independent ER function, and (3) ER-independent growth signaling. The established cell lines of category (1) showed increased expression of steroid metabolizing enzymes to produce agonist for ER. The category (2) was ligand-independent activation of ER, mainly via intracellular phosphorylation signaling pathway, which has been well investigated so far in many laboratory. The category (3) showed decreased ER expression or loss of ER function. Some of them were depended no androgen signaling pathway. As a study for therapeutic approach for AI-resistance, the effect of SERD, mTOR inhibitor, pan- or specific-PI3K inhibitors, and CDK4/6 inhibitor on these resistant cell lines were explored. Furthermore, fulvestrant-resistant cell lines, evelorimus-resistant cell lines, PI3K inhibitor-resistant cell lines, and CDK4/6 inhibitor-resistant cell lines were established and examined the efficacy of the other drugs and their cross-resistances. The results of these investigation will provide useful information for overcoming the hormonal therapy resistance.